1. Field of the Invention
The present invention relates to a stable concentrated aqueous solution of cis-diamminedinitratoplatinum and its use in the preparation of stablized aqueous injectable solutions of cisplatin.
2. Description of the prior Art
The platinum compounds are a unique group of compounds in the antineoplastic group of agents. They were first noted to have an antibiotic effect by Rosenberg and his colleagues in 1965 [Rosenberg, B. et al, Nature (London) 205, 698-699 (1965)] and subsequently found by Rosenberg and his colleagues to be potent antitumor agents in animals [Rosenberg, B. et al, Nature (London) 222, 385-386 (1969)].
Structurally, they represent a complex formed by a central atom of platinum and surrounded by various arrangements of chlorine atoms or ammonia groups in either a cis or trans planar relationship. Two of the more commonly studied platinum compounds are diagrammed below: ##STR1## As can be seen, the compound cis-platinum (II) diamminedichloride has all its chloro and amino groups in a single plane. This compound, now know by the United States Adopted Name (USAN) cisplatin, has been synthesized according to the following reaction: ##STR2## [see Kauffman, G. B. et al, in Inorganic Synthesis, J. Kleinberg (Ed.), pages 289-245, McGraw-Hill Book Co., Inc., New York 1963].
Breusova-Baidala, Y. G. et al, in Akademia Nauk SSSR, No. 6, pp. 1239-1242 (June 1974), discuss the slow isomerization of cis-platinum (II) diamminedichloride in aqueous solution to the trans form.
Reishus, J. W. and Martin, D. S., in Journal of the American Chemical Society, 83, 2457-2462 (1961), describe the acid hydrolysis of cisplatin at 25.degree. C. and 35.degree. C. These studies were conducted in aqueous solutions at concentrations of 1.5.times.10.sup.-3 M, 2.5.times.10.sup.-3 M and 5.0.times.10.sup.-3 M, which correspond to 0.45, 0.75 and 1.5 mg/ml, respectively. The authors state that there was some ambiguity in locating the origin (i.e., "zero point") for the hydrolysis curves because the samples required from 10 to 30 minutes to dissolve completely even at those low concentrations.
Rozencweig, M. et al, in Annals of Internal Medicine, 86, 808-812 (1977), review the results of various pre-clinical and clinical investigations of the use of cisplatin in experimental tumors in animals as well as various types of human tumors. They point out that the investigational drug, available to qualified investigators through the Investigational Drug Branch of the Cancer Therapy Evaluation Program of the National Cancer Institute, was supplied as a white lyophilized powder in vials containing 10 mg of cisplatin, 90 mg of sodium chloride, 100 mg of mannitol (U.S.P.) and hydrochloric acid for pH adjustment. When reconstituted with 10 ml of sterile water for injection (U.S.P.). each ml of the resulting solution would contain 1 mg of cisplatin, 10 mg of mannitol and 9 mg of NaCl.
Talley, R. W. et al, in Cancer Chemotherapy Reports, 57, 465-471 (1973), describe the results of their Phase I clincal study of the use of cisplatin in the treatment of 65 human patients with a wide variety of neoplasms. As in the preceding publication, the drug was supplied to them by the National Cancer Institute in vials containing 10 mg of cisplatin, 90 mg sodium chloride and 100 mg of mannitol, for reconstitution with 10 ml of sterile water.
Certain information concerning the chemistry and pharmaceutical formulation of cisplatin is given on pages 1-5 and 31-32 of the publication entitled "CLINICAL BROCHURE, CIS-PLATINUM (II) DIAMMINEDICHLORIDE (NSC-119875)", H. Haldelsman et al, Investigational Drug Branch, Cancer Chemotherapy Evaluation Program, Division of Cancer Treatment, National Cancer (Revised August 1974). Pages 31 and 32 thereof concern the formulation of cisplatin supplied gratis by the N.C.I. to clinicians for their clinical evaluation in the chemotherapy of cancer and read as follows: